tratamiento de cancer de riñon y sarcomas

3. “ It is much more important to know
what kind of patient has a disease,
than to know what kind of disease a
patient has”
Caleb Parry. 18th Century physician, Bath.
“We used to think our fate was in our
stars. Now we know, in large
measure, our fate is in our genes”
J.DWatson. Time Magazine 20 March 1989

4. clinicaloptions.com/oncology
Expert Insight Into Advanced RCC Treatment
Background
 ~ 64,770 new cases of kidney/renal pelvis cancers will be diagnosed
in the US in 2012 with an estimated 13,570 deaths[1]
• ~ 75% are clear-cell RCC[2]
• ~ 25% to 30% of pts with RCC are diagnosed with metastatic disease[2]
Background and Treatment of mRCC
Before the Era
of Targeted
Agents
 Cytokine-based therapy was associated with a median PFS of
3-5 mos[3-5]
and median OS of 13 mos[6]
Current
Situation
 Targeted agents have resulted in substantial improvements in
treatment outcomes for patients with mRCC[5,7,8]
1. Siegel R, et al. CA Cancer J Clin. 2012;62:10-29. 2. Motzer RJ, et al. N Engl J Med. 1996;335:865-875.
3. Rini BI, et al. J Clin Oncol. 2008;26:5422-5428. 4. Escudier B, et al. Lancet. 2007;370:2103-2111.
5. Motzer RJ, et al. N Engl J Med. 2007;356:115-124. 6. Coppin C, et al. Cochrane Database Syst Rev.
2005;1:CD001425. 7. Mulders P. Eur Urol Suppl. 2008;7:577-578. 8. Ljungberg B, et al. Eur Urol.

5. 5
Renal Cell Carcinoma : Histologic and
Molecular Characteristics
Proximal Nephron Distal Nephron
Clear Cell
Carcinoma
(75-80%)
• LOH - 3p25
• VHL mutation
(40-60%)
• Hypermethylation
(5-20%)
Papillary Carcinoma
(15%)
Type 1
c-met
mutation
Type 2
FH
mutation
Oncocytoma
(5%)
Collecting
Duct,
Undifferen-
tiated
(rare)Chromophobe
(5%)

6. Motzer, R. J. et al. J Clin Oncol; 24:5601-5608 2006
Fig 1. VHL pathway in clear-cell cancer of the kidney with examples of agents, temsirolimus (or RAD001), bevacizumab,
sunitinib (or sorafenib, pazopanib), and where they target the pathway are demonstrated
Pazopanib

7. clinicaloptions.com/oncology
Expert Insight Into Advanced RCC Treatment

8. Pazopanib: Mechanism of Action

9. Carcinoma de Células Renales. Tratamiento
Cirugía (Nefrectomía citoreductiva)
Inmunoterapia
Quimioterapia
Radioterapia
Medicamentos usados en el pasado y en el
presente
Futuro: Nuevos medicamentos antiangiogénicos

10. Terapia Sistémica en Carcinoma de Células
Renales
N°N°
PacientesPacientes
N°N°
EstudiosEstudios
Indice de RespuestaIndice de Respuesta
ObjetivaObjetiva
ReferenciaReferencia
QUIMIOTERAPIAQUIMIOTERAPIA 13471347 5151 55 Motzer & Russo, 2000Motzer & Russo, 2000
INTERFERON ALFAINTERFERON ALFA 10421042 2929 1212 Wirth, 1993Wirth, 1993
IL-2 DOSIS ALTAIL-2 DOSIS ALTA
en boloen bolo
537537 1010 1919 Law et al, 1995Law et al, 1995
IL-2 otra,IL-2 otra,
en hospitalizadosen hospitalizados
650650 2222 1515 Law et al, 1995Law et al, 1995
IL-2 DOSIS BAJA,IL-2 DOSIS BAJA,
en externosen externos
104104 66 2020 Law et al, 1995Law et al, 1995
INTERFERON ALFAINTERFERON ALFA
+ IL-2+ IL-2
607607 2323 1919 Vogelzang, 1993Vogelzang, 1993
Motzer RJ.Motzer RJ. JAMAJAMA 2006;295(21):2516-25242006;295(21):2516-2524

13.  Many kidney cancers are associated with a kinase
mutation responsible for angiogenesis factors
overexpression
 TKIs are targeted therapies: increasing response
and reducing side effects.
13

14. 14
SunitinibSorafenib Pazopanib
Kinase affinity profile
Ki app (nM)
VEGFR-1 10
VEGFR-2 4
VEGFR-3 6
PDGFR-α 2
PDGFR-β 5
C-Kit 15

15. 15

17. 17

18. 18
Marco Antonio Arap, New directions in the management of renal cell carcinoma
2007

19. 19
SURGERY
CLI NI CAL
TRI ALS
DRUG TREATMENTS
How to decide on treatment

21. clinicaloptions.com/oncology
Expert Insight Into Advanced RCC Treatment
Patient Management and Therapy Selection
in Advanced RCC: Considerations
 Previous nephrectomy
– Patients with intact primary tumor may benefit from surgical resection
 Tumor histology
– Evidence supporting the current therapeutic paradigm is largely limited to clear-cell
RCC
 Extent of metastases
– Patients with 1-3 metastatic sites or those with metastases affecting QoL may
benefit from additional treatment interventions including surgery, radiation, and/or
bone-modifying agents
 Previous systemic therapy
 Preexisting comorbidities
 Patient considerations
– Cost
– Convenience vs compliance

22. clinicaloptions.com/oncology
Expert Insight Into Advanced RCC Treatment
Interactive Decision Support Tool (IDST):
1 Tool, 3 Expert Recommendations
In the IDST (available at: http://clinicaloptions.com/RCCInsight), the above variables were used to make
treatment decisions.

23. clinicaloptions.com/oncology
Expert Insight Into Advanced RCC Treatment
An Expert Insight Is Shown With Each
Expert’s Treatment Recommendations
RCC IDST. Available at: http://clinicaloptions.com/RCCInsight.

24. 1. Extent of your cancer?
2. The standard treatment?
3. Side effects of treatment?
4. Anything to alter the standard recommendation?
5. Clinical trials?
6. What will your doctor recommend?
7. Do you agree?
Particular issues in kidney cancer
Scenarios
How to decide on treatment

25. 25
RESPONSE SORAFENIB SUNITINIB PAZOPANIB
Objective response 10% 31% 30%
Complete <1% 0% <1%
Partial 10% 31% 30%
Stable disease 74% 48% 38%
PFS 5,5 month vs 2,8
month (placebo)
11 month vs
5month (Ifn-a)
9,2 month vs 4,2
month (placebo)
OS 19,3 month vs 15,9
month (placebo)
26,4 month vs
21,8 month (Ifn-
a)
21,1 month vs 18,7
month (placebo)

26. Treatment naïve
Cytokine
Refractory
OS
PFS PFS
Sorafenib
5,8 mos.
(Phase II results only)
5,9 mos. 10,7 mos*.
Sunitinib 11 mos. 8,7 mos. 26,4 mos.
Pazopanib 11,1 mos. 7,4 mos. 21.1 mos.
* : Cross-over
26

27. Sore mouth Tiredness Feeling sick
Diarrhoea Hand & foot blisters Rash
Mood changes
High blood
pressure
Underactive
thyroid
Hair loss
S id e e f f e c t s a n d q u a lit y o f lif e

29. 29
Looking at Adverse effects…Looking at Adverse effects…
Side effect Sorafenib
(All
Grades)
Sunitinib (All
Grades)
Pazopanib (all
grades)
Fatique 29% 51% 19%
Hypertension 17% 28% 40%
Neutropenia 18% 25% 34%
Thrombopenia 12% 31% 32%
Rash/desquamation 28% 20% <1%
Diarrhea 48% 53% 52%
Nausea 19% 44% 26%
Anorexia 14% 40% 22%
Hand-foot
desquamation
33% NA 6%
Alopecia 27% 24% 8%
Dyspnea 14% 51% 7%

30. 30
Sorafenib
(All
Grades)
Sunitinib (All
Grades)
Pazopanib (all
grades)
Fatique 29% 74% 19%
• Hypothyroidism plays a major part in treatment-induced fatigue

31. 31
Sorafenib Sunitinib Pazopanib
Hypothyroidism 41% 85% 7%
Hypothyroidism related to tyrosine kinase inhibitors: an emerging
toxic effect of targeted therapy
Pazopanib must be less inhibiting a kinase implied in the thyroid
function
Available hypothesis are:
•Inhibition of iodine uptake
•Inhibition of thyroid peroxydase
•Regression of the gland vascularisation

32. 32
Hypertension all grade Grade 3/4
SORAFENIB 17% 4%
SUNITINIB 30% 8%
PAZOPANIB 40% 4%

33. 33
 myelosuppression is observed with the 3 Tyrosine Kinase
Inhibitors.
R KUMAR; Br J Cancer. 2009 November 17; 101(10): 1717–1723.
Frequency of Myelosuppression grade 3/4
TKI’s Sorafenib Sunitinib Pazopanib
Neutropenia 5% 12% 1%
Thrombocytopenia 1% 8% 1%

34. 34
 VEGFR are essential for hematopoiesis and one of the
main target of those TKIs.
Ki app (nM)
Sorafenib Sunitinib Pazopanib
VEGFR-1 10 229 15
VEGFR-2 4 51 8
VEGFR-3 6 30 10
R KUMAR; Br J Cancer. 2009 November 17; 101(10): 1717–1723.

35. 35
Cellular IC50 for inhibition
IC50 (nM)
Receptors Sorafenib Sunitinib Pazopanib
C-Kit 15 0.45 2.4
Flt-3 22 0.6 230
 Other Receptors are implied in haematopoiesis: Flt-3; C-
Kit
R KUMAR; Br J Cancer. 2009 November 17; 101(10): 1717–1723.

36. 36
Global health status / quality of life was compared
using prespecified HRQoL indices
-EORTC-QLQ-C30
-EQ-5D Index
-EQ-5D-VAS
There was no difference between pazopanib and
placebo (P > 0.05) at any of the on-therapy
assessment time points.
Cora N. Sternberg A randomized, double-blind phase III study of pazopanib in treatment-naive and
cytokine-pretreated patients with advanced renal cell carcinoma, 2009

37.  Pazopanib really reduces adverse effects of TKI
treatment in RCC
 Adverse effects will now play a keyrole in the TKI
developpement strategy
 Will the the upcoming molecule be better than
pazopanib ?
37

55. Soft Tissue Sarcomas
July 24, 2017

56. Introduction
 Rare: only 8300 new cases annually in U.S.
 3900 die annually from STS
 Mesodermal origin

65. 00
2020
4040
6060
8080
100100
1960 1970 1980 1990 2000 2010 2020 2030 20401960 1970 1980 1990 2000 2010 2020 2030 2040

66. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised,
double-blind, placebo-controlled phase 3 trial
Winette TA van der Graaf, MD, Jean-Yves Blay, MD, Sant P Chawla, MD, Dong-Wan Kim, MD, Binh Bui-Nguyen, MD, Paolo
G Casali, MD, Patrick Schöffski, MD, Massimo Aglietta, MD, Arthur P Staddon, MD, Yasuo Beppu, MD, Axel Le Cesne, MD,
Hans Gelderblom, MD, Ian R Judson, MD, Nobuhito Araki, MD, Monia Ouali, MSc, Sandrine Marreaud, MD, Rachel Hodge,
MSc, Mohammed R Dewji, MSc, Corneel Coens, MSc, George D Demetri, MD, Christopher D Fletcher, MD, Angelo Paolo
Dei Tos, MD, Peter Hohenberger, MD and on behalf of the EORTC Soft Tissue and Bone Sarcoma Group and the
PALETTE study group
The Lancet
Volume 379, Issue 9829, Pages 1879-1886 (May 2012)
DOI: 10.1016/S0140-6736(12)60651-5
Copyright © 2012 Elsevier Ltd Terms and Conditions

67. Figure 1
Source: The Lancet 2012; 379:1879-1886 (DOI:10.1016/S0140-6736(12)60651-5)
Terms and Conditions

69. Figure 2
Source: The Lancet 2012; 379:1879-1886 (DOI:10.1016/S0140-6736(12)60651-5)
Terms and Conditions

70. Figure 3
Source: The Lancet 2012; 379:1879-1886 (DOI:10.1016/S0140-6736(12)60651-5)
Terms and Conditions

72. RCC
Lung cancer
STS
Ovarian Ca.
Breast Ca.
Cervical Ca.
Glioblastoma
Nasopharyngeal
Thyroid Ca.
Mesothelioma
Lung Cancer
Breast Ca.
Neuroendocrine ca.
Prostate Ca.
Phase II studies
Pazopanib: Development Settings
Phase III studies

73. Discovery Performance Units
Smaller, Focused, Empowered, Accountable
Signal Transduction Metabolism
EpigeneticsStem CellBiopharmaceutical
Confidential